SUMMARY?OVERALL. The Harvard Aging Brain Study (HABS) was established nine years ago to elucidate the impact of the hallmark proteinopathies of Alzheimer?s disease (AD), i.e., amyloid-beta (a?) and tau, as assessed by PET imaging, in clinically normal older individuals. This is a competing renewal application for a third cycle of the HABS Program Project Grant (PPG) to continue our longitudinal cognitive and multi-modality imaging assessments of an extremely dedicated and richly phenotyped cohort of participants (currently age 51- 94, with diversity in ethnicity and socioeconomic status), and to leverage innovative technology to advance our quest to better understand cognitive aging and preclinical AD. We have made excellent progress in achieving the scientific goals of our second grant cycle, with over 100 research publications during the past four years that have informed ongoing prevention trial designs and international initiatives on the study of AD and other age-related pathologies. Our overall goals in this renewal are to: 1) Go earlier: investigate the earliest stages of a? and tau accumulation, evaluating specific anatomic patterns of progression, and the interactions of these pathologies in the ?pre-preclinical? phase of AD. 2) Go broader: investigate potential modulating factors, such as vascular risk, physical activity, and systemic inflammation that may independently contribute to cognitive decline, and interact with a? and tau to accelerate cognitive decline. 3) Go deeper: explore novel measures of synaptic integrity and utilize multifaceted digital technology to capture specific alterations in cognitive processes. 4) Go faster: enable more rapid and efficient assessment of change in imaging and cognitive measures over shorter time intervals, and ultimately predict progression on clinically meaningful outcomes. We propose five Cores, including a new Biomarker Core, that will support four Projects: Project 1: Investigate longitudinal a? and tau PET relationships and identify in vivo pathoanatomic stages detectable over the course of preclinical AD. Project 2: Investigate the contribution of other factors that modulate clinical decline, including vascular disease, physical activity, and exploratory blood biomarkers of neural injury and inflammation. Project 3: Evaluate longitudinal multi-modality imaging measures of synaptic function and explore a novel PET tracer of synaptic integrity. Project 4: Investigate the determinants of cognitive decline, optimize rapid detection with novel digital measures, and establish the clinical meaningfulness of early cognitive changes. This HABS PPG renewal will leverage an outstanding group of multidisciplinary investigators, access to cutting-edge imaging and cognitive assessment technology, and an extremely well-characterized cohort with some of the longest tau PET follow up in existence. The additional longitudinal assessments will allow us to determine the factors that promote healthy brain aging vs. those that confer susceptibility to accumulating a? and tau, and vulnerability vs. resilience to cognitive decline in the setting of early AD pathology, with the ultimate goal of accelerating progress towards the effective prevention of cognitive decline along the trajectory of preclinical AD.